Research

African Integrative Evolutionary Genomics

We combine field work, laboratory work, and computational approaches to address fundamental questions about modern human evolutionary history and the genetic architecture of traits related to adaptation and disease risk in Africa. We are using an integrative genomics approach, incorporating genomic, proteomic, epigenetic, transcriptomic, metabolomic, and microbiome data obtained from ethnically diverse Africans living in distinct environmentsto identify genetic and environmental factors that play a role in a number of anthropometric, metabolomic, cardiovascular, and immune related traits (Figure 1).

We incorporate genomic, proteomic, epigenetic, transcriptomic, metabolomic, and microbiome data obtained from ethnically diverse Africans living in distinct environments to identify genetic and environmental factors that play a role in a number of anthropometric, metabolic, cardiovascular, and immune related traits.

Many of these traits are likely to play a role in adaptation and some may play a role in disease susceptibility. We are characterizing gene and transcription networks to study how naturally occurring genetic and structural variation perturbs them. We are also studying how these networks are impacted by variable environmental factors such as lifestyle, diet, drug response, and infectious disease exposure. Additionally, we are examining patterns of genetic variation at the genome level among modern humans and non-human primates in order to elucidate the evolutionary forces (mutation, gene conversion/recombination, migration, drift, selection) that shape and maintain genetic variation in contemporary populations. These data are being used to reconstruct historical demographic and population differentiation events (including population expansion and contraction, subdivision, and migration) and to test hypotheses of modern human origins, including the possibility of introgression of archaic and modern human genomes.

African Genomic and Phenotypic Diversity Project

Most studies of human genomic variation and the genetic architecture of complex traits have focused on non-African populations. However, Africa is a critical region to study since it is the site of modern human origins, contains the greatest levels of human genetic variation (Figure 2), and is the source of the worldwide range expansion of modern humans in the past 100,000 years. Africa also has a high prevalence of several infectious diseases including HIV, malaria, and TB, resulting in millions of deaths per year. Additionally, several common complex diseases occur at higher frequency in African Americans, and are rapidly on the rise in urban regions of Africa, including hypertension, obesity, and type II diabetes. Differences in diet, climate, and exposure to pathogens among ethnically and geographically diverse African populations are likely to have produced distinct selection pressures, resulting in local genetic adaptations, some of which may play a role in disease susceptibility.

The circles are colored according to the proportion of ancestry. Populations have been pooled by geographic regions and/or language classification. Our study of genome-wide variation in over 3200 Africans, the largest study of nuclear variation to date, demonstrates the extraordinarily high levels of genetic variation within and between populations in Africa, likely due to their unique demographic history as well as local adaptation to distinct environments.

Given the high levels of genetic diversity observed, even in small geographic regions, this study demonstrates the necessity to include a diverse set of Africans in human integrative genomic studies.

To address the disparity of human genomic studies in Africa, we and African collaborators have assembled an extensive and unique collection of DNA samples from >9,000 geographically and ethnically diverse Africans with distinct diets (hunter-gatherers, pastoralists, agriculturalists) and living in diverse environments with differing pathogen exposure (Figures 3). Additionally, for these samples we have detailed ethnographic and nutritional information as well as detailed phenotype data for a wide range of anthropometric, cardiovascular, metabolic, and immune related traits. Great care is taken to conduct this research in an ethical manner. We have undergone extensive ethical review and approval at the institutional and national level in each African country, obtained group and individual consent, and returned results to participants whenever possible. An additional goal is to help train African scientists and students and to help build resources within Africa for doing human genomics research.

Figure 3. Field work in Africa.

In collaboration with our African colleagues, we are analyzing genomic data from this unique set of samples. From these studies, we will gain valuable knowledge of the genetic structure of African populations and the identification of markers that will be useful in gene mapping studies; we will learn about the correlation of environmental, cultural, linguistic, and genetic variation; we will be able to obtain estimates of demographic parameters and to test hypotheses of modern human origins and more recent population migration and differentiation events; we will identify functional regulatory elements that influence gene expression; we will identify genomic variants and pathways that play a role in human adaptation, phenotypic variation, and disease risk in African and African diaspora populations. Because non-African populations generally contain a subset of variation present in Africa, and because of low-levels of linkage disequilibrium in African populations, these studies will also be informative for fine-mapping of genetic variants associated with normal variable traits and disease risk in non-Africans.

KEY PUBLICATIONS

Gomez, F., J. Hirbo, and S.A. Tishkoff (2013) African population genetic history and evidence for local adaptation in African populations. Who are we? Human diversity and race from a contemporary genetics perspective. Chakravarti, A. (eds.) Cold Spring Harbor Press, In Press.

The Genetic Basis of Resistance to Infectious Disease

It is likely that infectious disease has played a major role in human evolution and in shaping genetic variation in the human genome. Thus, one focus of my laboratory is the study of human genetic variation and the evolutionary history of genes involved in resistance against infectious disease. We are characterizing patterns of genetic variation in candidate genes for resistance/susceptibility to malaria, TB, HIV, and trypanosomes in a set of globally diverse populations, but with an emphasis on African populations. Our goal is to identify functionally significant genetic variation that plays a role in susceptibility to infection. In addition, we are collaborating with laboratories that are studying genetic variation in the pathogens causing these disorders in order to examine co-evolution of infectious agents and their human hosts. Recent examples of this work include studies of G6PD, ICAM1, and glycophorin genes that play a role in malaria resistance and the APOL1 gene that plays a role in resistance to trypanosome infection, but is also associated with risk for kidney disease in African populations.

Figure 4.

(from Tishkoff, et al.Science, 2001)

Microsatellite haplotypes of chromosomes containing G6PD deficiency mutations (Mediterranean (M), A, and A-) as well as normal chromosomes (B and N). We see significantly higher linkage disequilibrium on the chromosomes containing G6PD deficiency mutations, consistent with a signature of natural selection, and we see that the African A and A- variants arose independently on a different chromosome background from the M variant, consistent with convergent evolution due to resistance from malaria infection.

The Genetic Basis of Adaptation in Humans

We currently know little about how changes at the genetic level correlate with phenotypic changes and adaptation to novel environments during recent human evolutionary history. Additionally, it has been hypothesized that genetic mutations associated with common complex diseases (e.g. hypertension, diabetes, obesity, asthma, arthritis, allergies, etc.) may be at high frequency in modern populations because they were adaptive in ancient environments. Thus, characterization of signatures of natural selection in genes that are of adaptive significance may be of use for identifying functionally significant variants, some of which may play a role in human disease. We are particularly interested in identifying local adaptation in culturally and geographically diverse Africans, because of the possibility that selective forces, and genetic variants, may be geographically restricted. We are also interested in developing and applying methods for distinguishing balancing selection, soft selective sweeps (i.e. selection from standing variation), and selection of loci involved in complex traits. Recent examples of our studies of local adaptation in Africa includes the identification and characterization of natural selection at loci that play a role in lactose tolerance in African pastoralists (Figure 5), the genetic basis of adaptation to high altitude in Ethiopia, and the genetic basis of the short stature trait in Western African Pygmies (in addition to the studies of adaptation at genes involved in infectious disease resistance described above).